Intestinal Epithelial Cell-derived Osteopontin Protects Against Metabolic Dysfunction-associated Steatohepatitis by Modulating Bile Acid Composition and the Gut Microbiome

Abstract

BACKGROUND & AIMS: The gut-liver axis plays a critical role in metabolic dysfunction-associated steatohepatitis (MASH). Osteopontin (OPN, encoded by SPP1) is implicated in chronic liver disease; however, its expression in intestinal epithelial cells (IECs) and role in MASH remain unclear. METHODS: We evaluated intestinal OPN expression during MASH progression in patients. To determine the function of IEC-derived OPN, we generated Spp1 knock-in (Spp1(KI IEC)) and knock-out (Spp1(?IEC)) mice and fed them a high-fat, high-fructose, high-cholesterol diet to induce MASH. RESULTS: IEC OPN expression decreased with MASH progression and was inversely associated with liver injury. Loss of Spp1 in IECs exacerbated MASH, whereas overexpression or oral OPN administration was protective. Spp1(?IEC) mice exhibited increased hepatic inflammation, disrupted IEC morphology, elevated IEC apoptosis, reduced epithelial cell turnover, and heightened intestinal permeability. They also showed hepatic 16s rRNA presence and elevated conjugated bile acids (BAs), particularly taurocholic acid and taurodeoxycholic acid, in portal serum. These BAs promoted hepatocyte injury and activated liver macrophages, enhancing inflammation both in vitro and in vivo. Fecal microbiome analysis revealed reduced abundance of bile salt hydrolase-expressing bacteria. Fecal microbiota transplantation from Spp1(?IEC) mice or treatment with a bile salt hydrolase inhibitor further worsened MASH. CONCLUSIONS: IEC-derived OPN protects against MASH by modulating BA composition and shaping the gut microbiome.